Ras oncogenes are the most frequently identified activated oncogenes in human tumors (1-3). It is known that the ras oncogenes encode 21,000 dalton G-proteins (p21ras) which play an essential role in growth factor signal transduction, proliferation and malignant transformation (1-7). Association of p21ras with the plasma membrane is required for its transforming activity (8,9). Post-translational events leading to membrane association of p21ras have previously been disclosed (10-14). The p21ras proteins are first made as pro-p21ras in the cytosol where they are modified on cysteine 186 of their carboxyl terminal sequence CA.sub.1 A.sub.2 X (C=cysteine, A.sub.1 and A.sub.2 =isoleucine, leucine or valine and X=methionine or serine) by the cholesterol biosynthesis intermediate farnesyl pyrophosphate (FPP). This farnesylation reaction is then followed by peptidase removal of the A.sub.1 A.sub.2 X tripeptide and carboxymethylation of the remaining cysteine. The processed p21ras proteins associate with the inner surface of the plasma membrane and are further modified on cysteines 181-184 by another lipid, palmitic acid (10-14).
p2lRas farnesyltransferase, the enzyme responsible for catalyzing the transfer of farnesyl, a 15-carbon isoprenoid, from FPP to the cysteine of the CA.sub.1 A.sub.2 X carboxyl terminus of p21ras, has been purified to homogeneity from rat brain (15,16). The enzyme is a heterodimer composed of .alpha. and .beta. subunits of molecular weights 49 and 46 kDa, respectively (17). The .beta. subunit has been shown (17) to bind p21ras and the .alpha. subunit is believed to bind FPP. Because p21ras farnesylation and subsequent membrane association are required for p21ras transforming activity, it has been proposed that p21ras farnesyltransferase would be a useful anticancer therapy target. Accordingly, an intensive search for inhibitors of the enzyme is underway (18-24). Potential inhibitor candidates are CA.sub.1 A.sub.2 X tetrapeptides which have been shown to be farnesylated by p21ras farnesyltransferase and appear to be potent inhibitors of this enzyme in vitro (15,18,21-24). Competition studies have demonstrated that CA.sub.1 A.sub.2 X peptides with the greatest inhibitory activity are those where A.sub.1 and A.sub.2 are hydrophobic peptides with charged or hydrophilic residues in the central positions demonstrating very little inhibitory activity (18,21,23).
The research efforts directed towards farnesyltransferase and the inhibition of its activity are further illustrated by the following patents or published patent applications: